Although frailty is generally considered to be a geriatric syndrome, individuals with chronic diseases, including chronic kidney disease (CKD) are at risk for premature frailty. Many patients on hemodialysis are frail, including a sizeable proportion of those under age 65. Frailty is a syndrome resulting from cumulative declines in multiple physiologic systems, leading to impaired homeostatic reserve and decreased capacity to withstand stress. Operational definitions of frailty vary, but two general approaches have emerged: a deficit accumulation approach, in which an individual's impairments and conditions are summed to create a frailty index and a physical frailty phenotype characterized by a set of components that include weight loss, exhaustion, low physical activity, and poor physical performance or self-reported physical function or various proxies thereof. Frailty is associated with higher risk of adverse outcomes, such as hospitalization and death among community-dwelling elders and among patients receiving maintenance dialysis, in whom the prevalence of frailty is much higher than even the general elderly population. Studies exploring correlates of frailty in the dialysis population have focused on the frailty phenotype approach and have emphasized demographics and comorbidities rather than potentially modifiable risk factors or pathophysiology. Specifically, the potential contributions of inflammation, hormone abnormalities, fluid overload, myokines, and polypharmacy have been under-investigated despite their potential for remediation. In addition, frailty has generally been treated as a stati condition, with studies determining outcomes after a single baseline assessment of frailty. A better understanding of the development, and in some cases, resolution of frailty could lead to better insight into its prevention and treatment. Finally, there has been little comparison of the prognostic information afforded by different definitions of frailty or by the individual components of frailty constructs among patients with end-stage renal disease (ESRD). The objective of this application is to thoroughly characterize frailty among patients on hemodialysis - its origins and clinical correlates, its trajectory, and factors related to its development and resolution. The rationale for undertaking these analyses is to gather information that can be used to prevent or mitigate frailty and its sequelae. We propose to leverage the data collected in a USRDS special study cohort, additional analyses of stored serum samples, and linkage to outcome information available in the USRDS to accomplish the following specific aims: Aim 1: Elucidate the underpinnings of physical frailty among patients on hemodialysis and identify potentially remediable correlates. Aim 2: Determine trajectories of frailty, focusing on risk factors for development and resolution of frailty. Aim 3: Determine the extent to which frailty predicts adverse outcomes, including death, hospitalization, development of disability, transition to a higher level of care, falls, and fractures.